Ulcerative colitis (UC) is a form of an inflammatory bowel disease (IBD) with a presumed genetic component. This produces an abnormal response of the immune system against intraluminar antigens whose main symptom is a chronic inflammation of the gastrointestinal tract accompanied by tissular destruction.
Although there is not a cure for UC, dietary modification may reduce the discomfort of a person with the disease and besides, the treatment with medicaments which can stabilize the patient are also indicated. Medicaments such as anti-inflammatory drugs (i.e. 5-aminosalicylate and corticosteroids), antibiotics and immunomodulators (i.e. azathioprine, 6-mercaptopurinam, cyclosporine and metotrexate), and immunosuppressant agents are commonly used. A disadvantage of these medicaments is that induce an unspecific suppression of the inflammatory process which provoke gastrointestinal side-effects such as nausea, diarrhea, abdominal pain, headache, and decrease of the immunoresponse of the patient. These gastrointestinal side-effects increase the risk of suffering infections, leucocytopenia or hepatic and pancreatic alterations, as well as osteoporosis, muscular dystrophy and weakness in long-term treatment with corticosteroids.
The treatment of UC is mainly based in the use of 5-aminosalicylic acid (5-AAS) as an active ingredient. A problem of the treatment with 5-AAS is the poor absorption of the active ingredient in the colon tract which provoke that the effective therapeutic concentrations are difficult to achieve. Therefore, it has been designed new formulations of 5-AAS which increase the absorption of the active ingredient. These formulations include microspheres, dimers or conjugates of 5-AAS which unfortunately continue maintaining the same gastrointestinal side-effects.
An alternative treatment for the restoration of the tissular damage in UC is the administration of peptides, in particular cytoprotective factors which are naturally secreted into the intestinal mucosa to restore its integrity. These factor can be alpha and beta transforming growth factor (TGF), trefoil factor, epidermal growth factor (EGF), keratinocyte growth factor (KGF), interleukin 11 (IL11), and a growing factor.
Control release formulations of some cytoprotective factors for their oral administration for its released in the intestinal lumen are known in the art. Thus, US 2007/26082 discloses an oral multiparticle pharmaceutical pellet which is form by an inner matrix layer containing peptides embedded in a matrix formed by a polymer with a mucoadhesive features.
The EGF is a growth factor that plays an important role in the regulation of growth, proliferation, and differentiation of cells by its binding to the epidermal growth factor receptor (EGFR). Human EGF is a 6045-Da protein with 53 amino acid residues and three intramolecular disulfide bonds. The high affinity binding of EGF to EGFR on the cell surface stimulates the intrinsic protein-tyrosine kinase activity of the receptor. The tyrosine kinase activity initiates a signal transduction cascade that results in a rise in the intracellular calcium levels, increases glycolysis and protein synthesis, and also increases the expression of certain genes including the gene for EGFR which results in the DNA synthesis and cell proliferation.
The EGF has been previously used in therapy. For example, EGF has been orally administered for its cicatrizing effect in gastro-duodenal lesions because the EGF acts before being degraded by the acidic conditions of the stomach. Besides, the EGF has been used for the treatment of UC only when administering via enema. This via has shown not to be effective in the treatment of UC in the ascendant portion of the colon tract. Besides, the subcutaneous administration of EGF alone or in combination with trefoil factor had shown its effectively in the restoration of wound and the treatment of UC.
EGF due to its peptide nature can modify spontaneously its structure during long-term packaging or in contact with biological fluids. This modification can compromises its half life and biological activity. The most probable ways of degradation of EGF are the oxidation of methionine residues, the desamination of asparagine residues and the formation of the succinamide in the position of aspartic acid residues. Besides, the exposure of EGF to some excipients during manufacturing conditions or storage of a pharmaceutical formulation, that is temperature, time, radiation intensity or humidity can provoke the denaturalisation of the ternary and quaternary structure (native structure) or fragmentation of the peptide chain promoting the response of the immune system against the EGF.
From what is known in the art it is derived that there is still the need of providing stable oral pharmaceutical compositions of epidermal growth factor where the active ingredient has a controlled release in the entire tract of the colon after a rapid passage through the stomach.